Emerging Applications of CAR-T Cell Therapy in Overcoming Resistance and Expanding Targets in Hematologic Malignancies: Insights from Recent Research

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment outcomes of patients with hematologic malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). However, issues such as antigen escape, T-cell exhaustion, and the limited efficacy of CAR-T cells in acute myeloid leukemia (AML) and T-cell leukemias still persist. This review aims to summarize human trials and achievements from 2015 with a focus on the innovations within the last two years. We discuss strategies to overcome resistance, including multi-target CARs, next-generation constructs, and combination strategies to treat resistant cancers. We also explore the ways to increase safety and access, including allogeneic CAR-T options. In this article, we propose CRISPR-enhanced CARs and synthetic biology-based allogeneic systems to enhance the efficacy and accessibility of CAR-T therapy with the aim of moving the field of oncology towards durable cures.

Graphical Abstract

Introduction

The development of chimeric antigen receptor T-cell (CAR-T) therapy revolutionized oncology treatment by creating engineered T cells that recognize tumor antigens through CARs. The outcome has been truly remarkable. The complete remission rates for relapsed/refractory B-ALL patients treated with Tisagenlecleucel range from 81 to 90% [1], and axicabtagene ciloleucel resulted in a 43% overall survival rate for DLBCL patients during a 5-year follow-up period [2, 3]. The BCMA-directed CAR-T therapy idecabtagene vicleucel has shown overall response rates (ORRs) of 73% in patients with MM. The FDA has approved six CAR-T products for B-cell malignancies since 2017, which target CD19 and BCMA. However, these successes have been tempered by lingering limitations. Antigen escape, or loss of CD19 or BCMA by tumor cells, leads to disease relapse in 30–50% of B-ALL patients, usually within 18 months [1, 4]. In multiple myeloma (MM), results from BCMA CART studies show a median progression-free survival (PFS) of less than 12 months for heavily pretreated patients [5]. T-cell exhaustion, as a result of chronic antigen exposure and immune suppressive microenvironments with increased TGF-β or IL-10, also contributes to reduced effectiveness [6, 7]. Collectively, AML and T-cell leukemias have limitations due to the antigen shared with normal immunologic T cells and fratricide [8, 9]. The last ten years, from 2024 to 2025, have seen various potential inventions emerge to address these obstacles. The CARs with multiple targets, such as CD19/CD22 or BCMA/GPRC5D, have been engineered to prevent antigen loss [10, 11]. The next generation CARs, which use IL-15 or STAT5 signaling pathways, are predicted to provide enhanced persistence [12, 13]. The inhibitory barrier in the microenvironment is expected to be overcome by combination therapies that include checkpoint inhibitors together with small molecular agents such as ibrutinib [14, 15]. Research on acute myeloid leukemia and T-cell malignancies has concentrated on developing new targets, including CD123 and CD7, as well as utilizing CRISPR technology to manage fratricide [16, 17]. The future looks promising for allogeneic CAR-T platforms because they will enable greater scalability, which could produce more affordable products and shorter manufacturing times [18, 19].

The review gathers information about recent CAR-T developments, mostly after 2015. Our evaluation will focus on hematologic malignancies because they contain the most significant studies, while we independently assess CAR-T resistance elimination and the geographic expansion of its application. The presentation will introduce two new pathways for future CAR-T development, which include CRISPR-driven precision CARs and synthetic biology-based allogeneic platforms. The high level of commitment exists because each successful opportunity brings us closer to achieving durable clinical responses and ultimately achieving cures, which all oncology professionals strive for.

Current Landscape of CAR-T Therapy

The journey of CAR-T therapy started with first-generation constructs that comprised a CD3ζ domain and struggled because the T cells couldn’t persist long enough [20]. The clinical success of CAR-T therapy emerged with second- and third-generation CARs when co-stimulatory domains (e.g., CD28 or 4-1BB) were added to the CAR construct [21, 22]. (Fig. 1). Six FDA-approved CAR-T products, including tisagenlecleucel and axicabtagene ciloleucel for CD19 targets and idecabtagene vicleucel for BCMA targets, are now available to treat B-ALL, DLBCL, MCL, FL, and MM [23, 24].

Fig. 1.

Evolution of CAR-T Generations. CARs of basic design can be divided into three regions as follows: (i) Extracellular domain for antigen recognition binding; it usually contains a single-stranded variable fragment derived from an antibody; (ii) transmembrane domain for anchor support to the plasma membrane; and (iii) Intracellular domain for T-cell activation. The Intracellular domain of first-generation CARs only has a CD3ζ-derived signaling module. Second-generation CARs also contain a co-stimulatory domain. Third-generation CARs contain two co-stimulatory domains. Co-stimulatory molecules include CD28, 4-1BB (CD137), CD27 and OX40 (CD134). Fourth-generation CAR T cells are also referred to as TRUCKs, which inducibly express chemokines such as IL-12. Fifth-generation CARs consist of a novel co-stimulatory domain to activate specific signaling pathways. CAR-T, chimeric antigen receptor T-cell; VL, variable region of light chain; VH, variable region of heavy chain; OX40, tumor necrosis factor receptor superfamily member 4; TRUCK, T cell redirected for universal cytokine-mediated killing; IL, interleukin; CD, cluster of differentiation; IL-2Rβ, IL-2 receptor β; JAK/STAT, Janus kinase/signal transducers and activators of transcription

The complete remission (CR) rate for B-ALL patients treated with CD19 CAR-T therapy reaches 81–90%, but 40–50% of patients experience relapse within two years because their cancer cells lose CD19 expression or develop CD19-negative B-progenitor cell populations [2, 25]. The 5-year overall survival (OS) for axicabtagene ciloleucel-treated DLBCL patients reaches 43% [3], while 70–90% of patients develop cytokine release syndrome (CRS) [2]. The KarMMa trial of idecabtagene vicleucel in MM patients achieved a 73% overall response rate and 8.8 months median progression-free survival [26]. But ciltacabtagene autoleucel has shown PFS extension to 22 months in certain patient groups [27]. The microenvironment of malignant cells, together with T-cell dysfunction and antigen loss of BA-cell malignancies, contributes to relapse mechanisms across different treatment indications [28].

Toxicity remains a major challenge. The CRS mediated by IL-6 and IL-1 occurs in 70–90% of patients; however, severe CRS occurs in 10–20% [29, 30]. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in 20–40% of patients and involves the potential risks of cerebral edema [31]. The cost of therapy exceeds $400,000, and 3 + weeks of manufacturing timeframe contributes to the limited availability of targeted CAR T-cells [32].

There are CD33- and CD123-displaying targeted CAR T-cells for AML that have provided overall response rates of 30–50%, while myeloid toxicity has been a major challenge [33]. CAR T-cells targeting CD5 and CD7 for T-ALL have also been studied, but fratricide of T-cells limits effectiveness [34, 35]. The upcoming data in 2024 and 2025 might refine the implementation of CAR T-cell therapy: updates from study ZUMA-5 show brexucabtagene autoleucel demonstrates 70% ORR in MC, and the use of dual BCMA/CD19 CARs in multiple myeloma can be efficacious in delaying relapse [36]. Table 1 details these outcomes, balancing success with ongoing challenges.

Table 1.

Key CAR-T trials in hematologic malignancies (2015–2025)

Cancer Type	Target	Therapy	Response Rate	Relapse Rate	Toxicity (CRS/ICANS)	Reference
B-ALL	CD19/CD22	Dual CAR	85% CR	30% at 18 m	70%/30%	[10]
DLBCL	CD19	CAR + Ibrutinib	70% ORR	25% at 12 m	60%/20%	[14]
MM	BCMA	IL-15 CAR	80% ORR	40% at 12 m	65%/25%	[12]
T-ALL	CD7	CRISPR CAR	60% CR	TBD	50%/15%	[17]
AML	CD123	CAR + Azacitidine	50% BR	TBD	80%/30%	[37]
MCL	CD19	Brexucabtagene	70% ORR	35% at 36 m	75%/25%	[23]
FL	CD19	Tisagenlecleucel	65% ORR	20% at 24 m	60%/15%	[38]

Overcoming Resistance: Novel Strategies

Multi-Target CAR-T Cells

Antigen escape is responsible for relapse in 30–50% of patients with B-ALL and MM [5, 10]. Multi-target CARs aim to mitigate this by targeting multiple antigens. For instance, CD19/CD22 CARs in B-ALL demonstrated an 85% CR rate and 70% RFS at 18 months [10]. In DLBCL, CD19/CD20 CARs reported a 75% ORR, and of these, 15% were antigen-negative relapses [39]. In MM, triple-target CARs, targeting BCMA/GPRC5D/SLAMF7, demonstrated a 90% reduction in tumor burden in preclinical models [40].

Next-Generation Constructs

The persistence of CLL and MM is affected by T cell exhaustion, according to research [7, 41]. The fourth- and fifth-generation CARs have incorporated IL-15 or STAT5 signaling [42]. The IL-15 BCMA CAR-T is undergoing clinical trials after showing threefold longer persistence in preclinical MM models [12]. The ORR of 60% has been observed in CLL patients treated with STAT5 CARs [43]. The microenvironment responses of armored CARs lead to the secretion of either IL-12 or IL-18. The IL-12 CAR-T treatment of DLBCL patients resulted in a 20% longer progression-free survival rate [44, 45]. The potential risks from cytokine management need to be tracked with caution [29].

Combination Therapies

Inhibition of the microenvironment by TGF-β or PD-L1 interferes with CAR-T [46]. Ibrutinib provided a 25% increase in overall survival (OS) with axicabtagene ciloleucel in patients with DLBCL [14, 15]. Pembrolizumab enhances BCMA CAR-T in multiple myeloma, increasing the ORR to 90% [47]. Lenalidomide prolongs progression-free survival (PFS) to 15 months with CAR-T therapy in multiple myeloma [48]. , while azacitidine induces sensitivity to CD123 CAR-T therapy in acute myeloid leukemia [23]. Optimal sequencing is still being investigated [49]. (Fig. 2).

Fig. 2.

Proposed Future CAR-T Platforms. A, B) Notch Platform for CAR-T Cells Production. Notch is a natural signal transduction receptor that recognizes the Delta ligand. The Notch–Delta interaction causes Notch to be cut, which releases the Notch intracellular domain. Subsequently, this intracellular domain translocates into the nucleus, where it regulates the expression of Notch target genes. In contrast, the synNotch system contains an extracellular antibody/nanobody domain that recognizes user-defined antigens. SynNotch is also cleaved by antigen recognition; however, it can induce the expression of user-defined target genes by releasing artificial transcription factors. C) Above is shown the autologous CAR T product manufacturing; precursor cell products are isolated from the patient mainly through apheresis, and final products are shipped to the local clinical facility. Below is shown the allogeneic CAR T product manufacturing; donor cells are collected and then selected using patient screening information. Final products are shipped from the cryogenic store to the local clinical facility. D) Delivery, engineering, and armoring approaches to enhance CAR-T cell efficacy. Advances in CAR T cell therapy for advanced glioblastoma were reported recently at three institutions. SynNotch: synthetic Notch receptor

Expanding Targets: Challenging Hematologic Malignancies

While CART therapy is highly successful in B-cell malignancies, it has yet to see the same outcomes in other hematologic cancers, such as T-cell leukemias or acute myeloid leukemia (AML). These results will require innovative targeting of biological complexity, and recent progress in animal models and human trials has taken place between 2024 and 2025. These trials will start to help address the challenges facing these more resistant diseases through the use of novel antigens, gene editing, and manipulation of the microenvironment.

T-Cell Malignancies

T-cell leukemias, such as T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCL), have resisted CAR-T therapy for an extended period due to fratricide—CAR-T cells that target pan-T-cell antigens like CD5 or CD7 can also destroy themselves during their expansion [9]. This has resulted in early attempts yielding poor T-cell yield and activity, as ORRs were less than 30% in preclinical models [34]. CRISPR/Cas9 technology has proven to be a game changer as it is used to knock out target antigens on CAR-T cells and prevent self-destruction of the CAR-T. A phase I trial of a CD7-knockout CAR-T in T-ALL in 2024 reported a 60% CR in 10 patients with median durations of remission over 12 months [17]. Patients underwent conditioning with fludarabine-cyclophosphamide to deplete host T cells, thereby minimizing competition, and CRS was grade 1–2 in 80% of patients. CAR-T targeting CD5 has been tested in PTCL xenografts, and decreased fratricide by 80% while still preserving effector function [34, 35].

In addition to fratricide, T-ALL’s immunosuppressive environment, characterized by high IL-10 and T regs, limits the efficacy of CAR T [50]. CD7 CAR T in combination with PD-1 blockade (e.g., nivolumab) can overcome this; a 2023 preclinical study demonstrated a 30% increase in tumor influx and a 50% reduction in Treg suppression using this combination in PTCL mouse models [50]. A phase II trial testing the CD7 CAR T + nivolumab combination is planned for 2025, utilizing post-CAR T nivolumab infusion to enhance effector function following CAR T infusion; further studies combining CD7 CAR T with nivolumab in humans must confirm this synergistic effect concerning immune response or toxicity. In another approach, TRBC1, a subunit of a T-cell receptor that is overexpressed in malignant T-cells and not expressed in most normal T-cells, is also being developed as a target for CAR T therapy. A recent study (2024) from a team in Italy reported that TRBC1 CAR T achieved a 70% reduction in tumors in PTCL mouse models, with no measurable fratricide [51]. A couple of challenges to address with this approach involve (1) the specificity of the target antigen, as TRBC1 differs among the T-cell subsets, and (2) the translation of pre-clinical findings into a successful manufacturing process at scale, but overall, these are very exciting prospects for addressing T-cell malignancies.

Acute Myeloid Leukemia

The heterogeneity of acute myeloid leukemia (AML) and the absence of a universal antigen, such as CD19, make it difficult to design CAR-T therapies [33]. CD33 and CD123, which are both expressed on AML blasts, are also expressed on healthy myeloid progenitors, meaning the emergence of severe cytopenias becomes possible [52]. An early phase I clinical trial planned for 2025 for a CD123 CAR-T with azacitidine in refractory AML resulted in a 50% reduction in blasts in 12 patients, with a median duration of response of 6 months [23]. Interest in CD123 emerged after azacitidine upregulation of CD123 on the AML blasts, thus promoting CAR-T targeting. Cytokine release syndrome (CRS) occurred in 20% of patients, experiencing grade 3 events, both types of CRS were treated with tocilizumab, and elevated neutrophil levels were treated with G-CSF. CD33 CAR-T was also available and tested in a cohort in 2024, with a 40% overall response rate observed. Hypomethylating agents (decitabine) increased the therapeutic efficacy by 25% [53]. The new targets introduce some level of precision in the treatment. CLL-1 (CLEC12A) was found to be enriched on AML stem cells but not on normal hematopoietic stem cells (HSCs). CLL-1 CAR-T achieved 70% tumor clearance in mouse models in 2023 [23]. The phase I trial of CLL-1 CAR-T in 2025 showed a 45% ORR in relapsed AML, and CLL-1 CAR-T did not show toxicity to HSCs [54]. Another potential target is FLT3 mutations, which are present in 30% of AML cases. A 2024 preclinical study showed that FLT3 CAR-T eliminated FLT3-mutant blasts without harming wild-type FLT3 cells [55]. FLT3 CAR-T in combination with FLT3 inhibitors (e.g., gilteritinib) enhanced progression-free survival (PFS) in preclinical mouse models, probably because it stopped antigen escape [55].

The allogeneic CAR-T therapy, which employs NK cells or gene-modified T cells, provides an immediate solution for AML treatment by avoiding the production timeline of traditional autologous therapies. The 2024 clinical trial of CAR-T NK cells targeting CD33 in AML patients yielded a 55% response rate and did not result in graft-versus-host disease (GvHD) [19]. The clinical trials of gene-edited T-cells with TALEN-mediated TCRαβ deletion for GvHD prevention began in 2025 to target CD123 and showed initial results with blast reduction at 60% [18]. The two approaches face challenges, including short NK-cell survival times and specific GEd problems with unwanted gene modifications, yet they indicate a new approach to treat AML through multiple target sites.

Safety and Accessibility Innovations

The clinical use of CAR-T is restricted, on the one hand, by toxicities (CRS, ICANS, and cytopenias), and on the other hand, by logistical barriers, such as the cost and time for the production of the CAR–T cells. Innovations in 2024–2025 are expected to enhance safety and access, which is required to enable the use of this CAR–T therapy in those settings beyond specialized practices.

Safety Enhancements

The CRS caused by the release of IL-6 and IL-1 occurs in 70–90% of patients, and it is severe (grade 3–4) in 10–20% of cases [29]. The phenomenon ICANS results from blood-brain barrier disruption and occurs in 20–40% of cases, with the possibility of seizures or edema in extreme cases [31]. witchable CARs enable the temporal control of activity using small-molecule drugs such as rapamycin. In a drug dilution study conducted in 2024, a trial utilizing a switchable CD19 CAR-T in DLBCL patients showed a 40% reduction in CRS incidence, with the patients receiving pulses of rapamycin to titrate activity towards therapeutic levels [56]. ICANS rates were reduced to 15%, with lower magnitude cytokines observed at peak. Suicide genes, such as iCasp9, provide an off-switch for CAR T-cells. A trial in 2023 of CAR T-cells for multiple myeloma resulted in CRS that was reduced to grade 4 after 24 h of administration of AP1903 to induce apoptosis [57]. Bispecific adapters function as soluble molecules to link chimeric antigen receptor-engineered T cells (CAR-T) to antigens, thus allowing dose adjustment for improved safety. The 2024 trial demonstrated that CD19 CAR-T treatment with CD19/CD3 bispecific adapter resulted in a 65% overall response rate among B-cell acute lymphoblastic leukemia (B-ALL) patients while reducing cytokine release syndrome (CRS) by 50% compared to fixed CAR-T therapies [12]. A 2025 study protocol used low-dose IL-1 receptor antagonists (anakinra) pre-treatment to reduce CRS severity by 30% in patients with multiple myeloma (MM). Medical interventions exist to enhance treatment safety for malignancies, particularly in patients who have complex medical conditions and are frail.

Accessibility Improvements

The expense of autologous CAR-T, at $400,000, and the 3–4-week production wait time limit access for a much broader group of patients [58]. Allogeneic CAR-T, which is made from ABA healthy donors or (induced) pluripotent stem cells (iPSCs), can be offered as an off-the-shelf approach. For example, in August 2024, a trial for NK-cell BCMA CAR-T, published in 2024, 55% ORR for 15 patients, no GvHD, and 7 production time days [19]. The innate ability of the NK cells to kill tumors and their short life span allows for less likelihood of rejection; unfortunately, less persistence diminishes durability should an allogeneic approach have persistence as an objective [59]. Another option is CRISPR-edited allogeneic T cells, with TCRαβ and CD52 knockouts, to combat host immunity. A trial for diffuse large B-cell synthetic (DLBCL), which was published in 2025, showed a 60% ORR and used alemtuzumab to deplete host lymphocytes [60]. Point-of-care biomanufacturing using automated bioreactors reduces cell product time to less than 48 h. A small 2024 pilot study in the B-cell acute lymphoblastic leukemia population demonstrated a 35% reduction in costs with bedside CAR-T therapy, achieving comparable outcomes to centralized services [61]. Cost-sharing models, such as an outcome-based pricing framework from 2023 with a 12-month progression-free survival, may reduce expenses by up to 50% [62]. All of these developments seek to decrease the cost of CAR-T products below $100,000 in order to provide access to a wider cross-section of health systems by 2030.

Future Approaches: A Vision for CAR-T

CAR-T therapy needs to develop precision capabilities together with scalability and flexibility for its future success. Two new approaches for re-imagining CAR-T future development in hematologic malignancies emerge from analyzing trends between 2024 and 2025.

CRISPR-Enhanced Precision CARs

CRISPR/Cas9 has revolutionized CAR-T therapy through its ability to eliminate antigens that attack each other [17]But this represents the initial stage of development. The development of CRISPR-edited CAR-T cells with distinct cytolytic features presents an opportunity to redesign the tumor microenvironment. Researchers conducted a 2025 study on AML using a CD123 CAR-T cell, which they modified to produce IL-12. The model achieved double the tumor clearance rate because it activated the body’s natural immune response to a previously inactive microenvironment [17]. The immune-stimulating effects of IL-12 on Th1 immunity and TGF-β suppression come with the danger of excessive inflammation, yet multiplex-genome-engineering methods could target IL-6 or TNF-α for silencing, according to our 2025 study findings [63].

The alternative strategy functions by altering the exhaustion circuitry. The 2024 DLBCL model shows that removing PD-1 and LAG-3 from CD19 CAR-T cells leads to a 50% longer persistence, and clinical trials are scheduled for 2026 [54]. The CRISPR variant base editing shows promise for targeting epigenetic regulators such as EZH2 through single-base modifications, which led to a 40% enhancement of effector function in multiple myeloma patients during 2023 [12]. The use of patient-specific edits, such as FLT3 mutation-targeting CAR-T therapy in AML, enables personalized treatments and enables researchers to use single-cell sequencing for identifying treatment targets and making commitments [64].

Synthetic Biology-Driven Allogeneic CAR-T

The scalability of the allogeneic CAR-T platform is constrained by persistence and rejection [18]. Synthetic biology strategies may provide a solution through engineered receptors that are responsive to cues specific to tumors. For example, we propose CARs utilizing synthetic Notch (synNotch) domains that can be activated by metabolites, such as lactate, which is abundant in the tumor microenvironment of acute myeloid leukemia (AML). Clinicians will enter into exhaustive knowledge base queries about Docker-Shell. A 2024 study in solid tumors employed synNotch CAR T cells that were activated by hypoxia, which resulted in an 80% reduction in tumor burden [65]. A related application in hematologic malignancies would target lactate or kynurenine, neither of which has been tested as of 2025 [66–68]. For enhanced safety, synthetic kill switches are being developed beyond iCasp9 approaches. In 2025, one version was developed using a plasma-membrane localized death receptor that is activated by light in mice with CAR T cells that use spatial control to activate CAR T cell apoptosis [13]. Adding to this approach is the possibility of engineering allogenic NK cells capable of secreting IL-15 for extended survival, as demonstrated in a trial in 2024 where NK CAR T cells have a doubled lifespan in multiple myeloma (MM) [19]. In agreement with the additive approaches described above, these platforms can be established via an iPSC bank, a vision for a universal CAR-T ecosystem by 2030, where patient efficacy and acceptable culture ownership can lead to acceptance of universal access and equity. (Table 2).

Table 2.

Resistance mechanisms and Counter-Strategies

Mechanism	Description	Solution	Example Outcome	Reference
Antigen Loss	Loss of CD19/BCMA	Multi-target CARs	70% RFS at 18 m	[69]
T-Cell Exhaustion	PD-1 upregulation	IL-15/STAT5 CARs	3x persistence	[70]
Microenvironment	TGF-β suppression	Armored CARs (IL-12)	20% PFS increase	[71]
Low Persistence	Early T-cell apoptosis	Lenalidomide combo	15 m PFS vs. 10 m	[70]
Antigen Dimness	Reduced target density	Bispecific adapters	60% ORR preclinical	[12]
Immune Evasion	HLA downregulation	NK-cell CAR-T	55% ORR in MM	[19]
Cytokine Storm	Excessive IL-6 release	Switchable CARs	40% CRS reduction	[72]

Conclusion

CAR-T therapy has shown significant progress during the past years, which demonstrates its potential to transform the field. The development of multi-target CARs together with ibrutinib combination therapies has resulted in better outcomes for B-ALL patients and DLBCL patients. The research into T-cell leukemias and AML shows remarkable progress through CRISPR-modified CAR-T, which produces significant remissions in T-ALL and blast reductions in AML when used with combination therapies. The implementation of safety protocols has controlled severe toxicities, and allogeneic platforms have improved accessibility by shortening timelines and reducing costs. Despite the progress made, multiple challenges still exist. The improved CAR designs have not eliminated relapse as a treatment challenge, and cytokine release syndrome, together with other toxicities, persist as treatment complications. The current treatment responses in AML and T-cell leukemias show promise, but their durability falls short of B-cell malignancy outcomes. The access to this treatment continues to expand, but low-resource settings still lag because of high costs and limited infrastructure. The ongoing need for advancement becomes essential because CAR-T needs to overcome these obstacles to achieve its full potential. The future holds potential for precision therapy through our proposed CRISPR CARs, which function as engineered cells that produce immune-modulating cytokines and resist exhaustion for sustained therapeutic effects. The combination of allogeneic CAR-T cells with synthetic biology capabilities to detect tumor-specific signals enables the development of a scalable therapeutic platform that ensures safety for all patients. The proposed concepts indicate that future therapies will achieve high effectiveness while being available to all patients and tailored to specific tumor types and individual risk profiles. The future state of CAR-T therapy demands clinical trials, together with scalable manufacturing systems and delivery equity, to become a reality. CAR-T therapy provides the potential to transform hematologic malignancies from manageable diseases into chronic conditions that can be eliminated through this field’s advancement.

Key References

• Huang, S., et al., Deciphering and advancing CAR-T cell therapy with single-cell sequencing technologies. Molecular Cancer, 2023. 22(1): p. 80.

  • ○ This reference is of outstanding importance because it has been studied in a state-of-the-art application of CAR-T cells with an approach to the use of single-cell sequencing technology and indicates the efficacy of this treatment method.
• Shi, M., et al., Bispecific CAR-T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nature Communications, 2024. 15(1): p. 3371.

  • ○ This reference is of importance because it firstly applies and he use of bispecific CAR-T cells to target two significantly promising markers in refractory: BCMA and CD19.

Author Contributions

Z. Sh., A.L., and S.B performed literature searching and analysis. Z. Sh. and S.S. wrote the primary draft. M.R.F. illustrated figures and tables. I. A conceptualized, supervised the study’s technical details, critically edited, and submitted the manuscript as the correspondence. All authors have reviewed and approved the final manuscript.

Funding

Not applicable.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Declaration of Generative AI and AI-assisted Technologies in the Writing Process

During the preparation of this work, the author(s) used ChatGPT in order to enhance the clarity, grammar, and flow of the writing. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Competing Interests

The authors declare no competing interests.

Clinical Trial Number

not applicable.